rs28943591

Variant names:

• chr5-119515014-G-A
• rs28943591
• NM_000414.4:c.1471G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-119515014-G-A
• chr5-119515014-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000414.4(HSD17B4):​c.1471G>A​(p.Ala491Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00495 in 1,585,784 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0035 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0051 (23 hom.)
• Consequence: HSD17B4 NM_000414.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15 O:1
• Conservation: PhyloP100: 3.84
• Publications: 14 publications found

Genes affected

HSD17B4 (HGNC:5213): (hydroxysteroid 17-beta dehydrogenase 4) The protein encoded by this gene is a bifunctional enzyme that is involved in the peroxisomal beta-oxidation pathway for fatty acids. It also acts as a catalyst for the formation of 3-ketoacyl-CoA intermediates from both straight-chain and 2-methyl-branched-chain fatty acids. Defects in this gene that affect the peroxisomal fatty acid beta-oxidation activity are a cause of D-bifunctional protein deficiency (DBPD). An apparent pseudogene of this gene is present on chromosome 8. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, May 2014]

HSD17B4 Gene-Disease associations (from GenCC):

• d-bifunctional protein deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• Perrault syndrome

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Perrault syndrome 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012981385).
• BP6: Variant 5-119515014-G-A is Benign according to our data. Variant chr5-119515014-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 194706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00355 (540/152178) while in subpopulation NFE AF = 0.00618 (420/67970). AF 95% confidence interval is 0.00569. There are 2 homozygotes in GnomAd4. There are 219 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSD17B4	NM_000414.4	c.1471G>A	p.Ala491Thr	missense_variant	Exon 17 of 24	ENST00000510025.7	NP_000405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSD17B4	ENST00000510025.7	c.1471G>A	p.Ala491Thr	missense_variant	Exon 17 of 24	2	NM_000414.4	ENSP00000424940.3

Frequencies

GnomAD3 genomes AF: 0.00354 AC: 539 AN: 152060 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000942

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00445

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00616

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00344 AC: 864 AN: 251252 AF XY: 0.00348

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00486

Gnomad ASJ exome AF: 0.000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.00563

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00509 AC: 7303 AN: 1433606 Hom.: 23 Cov.: 25 AF XY: 0.00499 AC XY: 3566 AN XY: 715194

African (AFR) AF: 0.000912 AC: 30 AN: 32888

American (AMR) AF: 0.00521 AC: 233 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.000617 AC: 16 AN: 25932

East Asian (EAS) AF: 0.00 AC: 0 AN: 39420

South Asian (SAS) AF: 0.000128 AC: 11 AN: 85670

European-Finnish (FIN) AF: 0.000543 AC: 29 AN: 53404

Middle Eastern (MID) AF: 0.00105 AC: 6 AN: 5696

European-Non Finnish (NFE) AF: 0.00620 AC: 6734 AN: 1086428

Other (OTH) AF: 0.00410 AC: 244 AN: 59474

GnomAD4 genome AF: 0.00355 AC: 540 AN: 152178 Hom.: 2 Cov.: 32 AF XY: 0.00294 AC XY: 219 AN XY: 74390

African (AFR) AF: 0.000939 AC: 39 AN: 41540

American (AMR) AF: 0.00445 AC: 68 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00618 AC: 420 AN: 67970

Other (OTH) AF: 0.00427 AC: 9 AN: 2108

Alfa AF: 0.00495 Hom.: 1

Bravo AF: 0.00418

TwinsUK AF: 0.00782 AC: 29

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00558 AC: 48

ExAC AF: 0.00311 AC: 378

Asia WGS AF: 0.000289 AC: 1 AN: 3470

EpiCase AF: 0.00780

EpiControl AF: 0.00711

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:7

Aug 19, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 16, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

HSD17B4: BP4, BS2 -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 15, 2019

Athena Diagnostics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:4

Mar 30, 2015

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ala516Thr in exon 18 of HSD17B4: This variant is not expected to have clinical s ignificance because it has been identified in 0.6% (48/8596) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs28943591). -

Jul 27, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: HSD17B4 c.1471G>A (p.Ala491Thr) results in a non-conservative amino acid change located in the MaoC-like dehydratase domain (IPR002539) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0034 in 251252 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is approximately 1.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in HSD17B4 causing D-Bifunctional Protein Deficiency phenotype (0.003), strongly suggesting that the variant is benign. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine ClinVar submitters (evaluation after 2014) cite the variant as benign (n=4) and likely benign (n=5). Based on the evidence outlined above, the variant was classified as benign. -

Dec 07, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Bifunctional peroxisomal enzyme deficiency Benign:2

Jan 12, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Bifunctional peroxisomal enzyme deficiency;C0685838:Perrault syndrome Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Perrault syndrome 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Bifunctional peroxisomal enzyme deficiency;C4551721:Perrault syndrome 1 Other:1

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T;.;T;.;.;.;T;.;T;.;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.95	.;D;D;.;D;D;D;D;D;D;D
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.013	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.028	D
MutationAssessor	Uncertain	2.6	M;.;M;.;.;.;.;.;.;.;.
PhyloP100		3.8
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-2.1	N;N;.;.;N;.;.;.;N;N;.
REVEL	Uncertain	0.36
Sift	Benign	0.098	T;T;.;.;T;.;.;.;T;T;.
Sift4G	Benign	0.24	T;T;.;.;T;.;.;.;T;T;.
Polyphen		0.62	P;.;P;.;.;.;P;.;.;P;.
Vest4		0.37
MVP		0.90
MPC		0.12
ClinPred		0.039	T
GERP RS		4.2
Varity_R		0.18
gMVP		0.76
Mutation Taster		=69/31	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs28943591; hg19: chr5-118850709;